ClinVar Genomic variation as it relates to human health
NM_001018005.2(TPM1):c.712C>T (p.Arg238Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001018005.2(TPM1):c.712C>T (p.Arg238Trp)
Variation ID: 43436 Accession: VCV000043436.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.2 15: 63062585 (GRCh38) [ NCBI UCSC ] 15: 63354784 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 24, 2015 Jun 1, 2016 Jul 15, 2014 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001018005.2:c.712C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001018005.1:p.Arg238Trp missense NM_000366.6:c.712C>T NP_000357.3:p.Arg238Trp missense NM_001018004.2:c.712C>T NP_001018004.1:p.Arg238Trp missense NM_001018006.2:c.712C>T NP_001018006.1:p.Arg238Trp missense NM_001018007.2:c.712C>T NP_001018007.1:p.Arg238Trp missense NM_001018008.2:c.604C>T NP_001018008.1:p.Arg202Trp missense NM_001018020.2:c.712C>T NP_001018020.1:p.Arg238Trp missense NM_001301244.2:c.712C>T NP_001288173.1:p.Arg238Trp missense NM_001301289.2:c.604C>T NP_001288218.1:p.Arg202Trp missense NM_001330344.2:c.604C>T NP_001317273.1:p.Arg202Trp missense NM_001330346.2:c.604C>T NP_001317275.1:p.Arg202Trp missense NM_001330351.2:c.604C>T NP_001317280.1:p.Arg202Trp missense NM_001365776.1:c.712C>T NP_001352705.1:p.Arg238Trp missense NM_001365777.1:c.712C>T NP_001352706.1:p.Arg238Trp missense NM_001365778.1:c.838C>T NP_001352707.1:p.Arg280Trp missense NM_001365779.1:c.712C>T NP_001352708.1:p.Arg238Trp missense NM_001365780.1:c.604C>T NP_001352709.1:p.Arg202Trp missense NM_001365781.2:c.604C>T NP_001352710.1:p.Arg202Trp missense NM_001365782.1:c.604C>T NP_001352711.1:p.Arg202Trp missense NC_000015.10:g.63062585C>T NC_000015.9:g.63354784C>T NG_007557.1:g.24947C>T LRG_387:g.24947C>T LRG_387t1:c.712C>T LRG_387p1:p.Arg238Trp - Protein change
- R238W, R202W, R280W
- Other names
- p.R238W:CGG>TGG
- Canonical SPDI
- NC_000015.10:63062584:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TPM1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
797 | 846 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
no assertion criteria provided
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May 27, 2013 | RCV000036356.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 15, 2014 | RCV000159384.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jul 15, 2014)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209330.2
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
The R238W variant in the TPM1 gene has been reported as a "pathogenic variant" in a publication investigating the technical sensitivity of a mutation detection … (more)
The R238W variant in the TPM1 gene has been reported as a "pathogenic variant" in a publication investigating the technical sensitivity of a mutation detection assay. Clinical information associated with R238W was not included in this publication (Zimmerman R et al., 2010). R238W is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The R238 residue is conserved across species. Mutations in nearby residues (D230N, A239T) have been reported in association with DCM, further supporting the functional importance of this region of the protein. Furthermore, R238W was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s). (less)
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Uncertain significance
(May 27, 2013)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280544.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg238Trp (R238W; c.712 C>T) in exon 8 of the TPM1 gene The testing lab refered to it as “published” because after being seen at LMM it was added to a DCM sequencing chip in a publication by Zimmerman et al. (2010) as a “pathogenic variant” (this is the group from LMM and Partners Healthcare; see the paper’s supplementary material). Because of this same reference, it is listed in HGMD. There is no segregation data available. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. The Arginine at this location is highly conserved across 10 vertebrate species for which information is available. Several adjacent residues on either side are also highly conserved. Variation at nearby residues has been associated with cardiomyopathy, which supports the functional importance of this region of the protein: Asp230Asn, Ala239Thr (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 1.0. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. However, these individuals are not ancestry-matched to our patient, who is of Mexican descent. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of April 15, 2014. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Mar 01, 2008)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060008.5
First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016 |
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs397516386 ...
HelpRecord last updated Dec 24, 2022
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.